Supervisors: Dr Tim Blower and Professor Rick Lewis

Having graduated from Durham University in 2018 with a first-class degree in Biomedical Science I chose to stay on to complete a research masters under the supervision of Dr Tim Blower. The project focussed on promoter binding by type IV antitoxins of Mycobacterium tuberculosis characterising the protein-promoter interactions biochemically and attempting to solve the antitoxin structures using crystallography. I was awarded the MSc in 2019 following assessment by a thesis. I developed an interest in the toxin-antitoxin systems of Mycobacterium tuberculosis and how these may one day be used for drug-discovery. I enjoyed working on protein structures and complementing this with biochemical characterisations. Following my MSc I have stayed on under the supervision of Dr Tim Blower having accepted a DTP to study the type II parDE toxin -antitoxin systems of Mycobacterium tuberculosis.

Project Title: Untangling topoisomerase inhibition by parDE toxin-antitoxin systems of Mycrobacterium tuberculosis

My PhD project focusses on characterising the two parDE toxin-antitoxin systems present in the Mycobacterium tuberculosis H37Rv genome. The toxins of these systems, ParE1 and ParE2, are suspected to target the essential enzyme DNA gyrase. M. tuberculosis has evolved to carry DNA gyrase as its only topoisomerase. This enzyme is capable of relaxing positively supercoiled DNA, introducing negative supercoils in an ATP-dependent manner, and also decatenation. This has made DNA gyrase an attractive target for therapeutics and is indeed targeted by antibiotics such as fluoroquinolones, an important class of drugs in the treatment of tuberculosis. Resistance to mainline drugs, including fluoroquinolones, is emerging, therefore investigating alternative mechanisms of gyrase inhibition, such as via ParE toxins, may provide insights into drug-discovery. The goals of the project are to characterise the parDE systems showing they function as a toxin-antitoxin system in vivo, solve the structures of the parDE complexes via crystallography, and investigate the toxin-gyrase interactions both biochemically and structurally. Structural characterisation is planned to include a combination of crystallography and cryo-electron microscopy.

Other activities

Gave a talk at the Federation of European Microbiological Societies conference 2019. The talk covered data on the type IV antitoxin-promoter interactions alongside structural characterisation and comparisons of type IV antitoxins.

Where did I get my PIPs

PIPS Internship Organisation Name 

Three Brother Brewing Co.

Location 

Teeside

When deciding on your internship, what did you want to experience and what did you hope to gain from that experience? 

I  mainly wanted to experience going into a very different environment and  working with a greater range of people with different backgrounds. I  knew this would aid the development of my communication skills and  increase my confidence in approaching new situations, solving a range of  novel problems. Additionally, as someone interested in the brewing  trade and with experience in the food & beverage industry, I wanted  to learn more about the processes involved and the industry in general. I  believe the internship was a success overall on these fronts.

Did you get the experience you were expecting and did you achieve the personal development you had hoped to make? 

Yes,  I actually think I got more out of the experience than I originally  expected. The overall brewing experience was a lot of fun, definitely  harder physically than I might have anticipated but that was a great  challenge. In terms of personal development, I feel I got really  involved in all aspects of the business from production to marketing and  sales; the sales experience pushed me a little out of my comfort zone  and I definitely feel more comfortable approaching new people now. The  project we initially decided on for the placement changed considerably,  and I had to develop some more general commercial problem solving skills  in order to really add value to the brewery. I felt this was a  particularly influential experience for me, as I think more about the  ‘big picture’ now and can structure larger and more complex problems  more comfortably.

Did you discover anything about yourself or make any achievements that you were not expecting? 

I  believe I have increased my workload from day-to-day after this  experience, working much more efficiently. Personally, I believe I have  become far more patient across the internship after working with a  greater range of people from different backgrounds and capabilities. In  terms of my own confidence, I think this has increased and I am more  comfortable and a different and novel environment; I feel more capable  of assessing new situations, adapting to new environments and solving  new problems.

Has the internship made you feel differently  about potential career options and has it helped to put the skills from  research into a broader context? 

Certainly has put my  research skills and project management abilities into a broader context  as I was able to pick up the required techniques quickly and adapt to  the new environment. I was later capable of managing other people’s time  stepping up to effectively run the brewery floor and support staff. The  internship has definitely assisted me in whittling down the options for  my career after the PhD. Having essentially gone into this brewery with  a scientific background, specialising in microbiology, I have realised  that science consulting is a great option for me moving forward. I  really enjoyed working with the directors of the brewery to identify  areas where my specialism was most impactful, but also to working  through more general business problems with the team in order to improve  the day-to-day operations. This experience highlighted that I am not  limited to the niche that my PhD has been focussed on, rather, my  skillset is very much applicable to a wide range of problems, especially  in a commercial environment.